Juan Yang1,2 · Haiqing Zhang2  · You Wang1  · Yuemei Luo2  · Weijin Zheng3  · Yong Liu1  · Qian Jiang1  · Jing Deng1,4 · Qiankun Liu1  · Peng Zhang1  · Hao Huang2  · Changyin Yu2  · Zucai Xu2  · Yangmei Chen1

1 Department of Neurology, the Second Afliated Hospital of Chongqing Medical University, Chongqing 400010, China 

2 Department of Neurology, Afliated Hospital of Zunyi Medical University, Zunyi 563000, China 

3 Department of Health Management, Afliated Hospital of Zunyi Medical University, Zunyi 563000, China 

4 Health Management Center, the Second Afliated Hospital of Chongqing Medical University, Chongqing 400010, China

Abstract

Epilepsy is a chronic neurological disorder affecting ~65 million individuals worldwide. Abnormal synaptic plasticity is one of the most important pathological features of this condition. We investigated how ubiquitin-specific peptidase 47 (USP47) influences synaptic plasticity and its link to epilepsy. We found that USP47 enhanced excitatory postsynaptic transmission and increased the density of total dendritic spines and the proportion of mature dendritic spines. Furthermore, USP47 inhibited the degradation of the ubiquitinated α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunit glutamate receptor 1 (GluR1), which is associated with synaptic plasticity. In addition, elevated levels of USP47 were found in epileptic mice, and USP47 knockdown reduced the frequency and duration of seizure-like events and alleviated epileptic seizures. To summarize, we present a new mechanism whereby USP47 regulates excitatory postsynaptic plasticity through the inhibition of ubiquitinated GluR1 degradation. Modulating USP47 may offer a potential approach for controlling seizures and modifying disease progression in future therapeutic strategies.

Keywords

Ubiquitin-specifc protease 47; Synaptic plasticity; Glutamate receptor 1; Protein degradation; Epilepsy

[SpringerLink]